Obesity is a major health problem, affecting over 30% of the U.S. population, and increasing morbidity and mortality. Obesity occurs when energy intake continuously exceeds energy expenditure. While energy intake is dependent primarily on food consumption, energy expenditure is multifactorial, depending on basal metabolism, adaptive thermogenesis, the thermic effect of nutrition (diet-induced thermogenesis, DIT), and physical activity. The central melanocortin system has been demonstrated to play a critical role in energy homeostasis in both rodent and man. Recent studies in the mouse reveal a critical role for the MC4-R in diet-induced thermogenesis. However, the central circuits through which the melanocortin system regulates thermogenesis have not yet been identified. Furthermore, while a variety of satiety and hunger factors, such as PYY and ghrelin, have recently been demonstrated to act on arcuate melanocortin neurons, the mechanism by which caloric intake is acutely sensed by the melanocortin system is unknown. In this proposal, we will employ multiple approaches including neuroanatomy and whole animal physiology to test the hypothesis that the central melanocortin system plays critical roles in the regulation of adaptive thermogenesis and DIT by regulation of autonomic and neuroendocrine systems relevant to energy metabolism. We will also begin to characterize the afferent neuronal and humoral signals that communicate information about caloric intake to the central melanocortin system. To accomplish these goals, we will first use injection into peripheral effector tissue of the trans-synaptic retrograde tracer, pseudorabies virus, to characterize the neuroanatomical substrate(s) through which the melanocortin system regulates thermogenesis. Next, we will determine the respective functional roles in thermogenesis of the various melanocortin-responsive brain nuclei identified neuroanatomically, by assaying oxygen consumption, sympathetic nerve firing and/or norepinephrine (NE) turnover in various thermogenesis effector tissues following melanocortin agonist injection into these nuclei. Finally, if time permits during the first funding period, we will begin to characterize the afferent neural and humoral inputs to these circuits by attempting to identify the afferent signaling mechanisms underlying melanocortin system mediated DIT. Together, these studies should greatly extend our understanding of the central control of energy homeostasis.